The intestine performs many functions, including the processes of digestion, selective absorption, and secretion. Yet, in addition to these functions, the intestine must also serve as a major barrier to prevent bacteria and/or endotoxin contained within the gut from invading systemic organs and tissues. Based on epidemiologic studies, the mucosal barrier to bacteria appears to be lost under certain clinical circumstances resulting in systemic sepsis. In fact, life threatening infections with gut-associated bacteria, in which no infective focus can be found even at autopsy, is a major clinical problem in burn patients, victims of trauma, and patients developing the multiple organ failure syndrome. We previously established that bacteria can cross (translocate) the gastrointestinal mucosal barrier and spread systemically in rodents subjected to thermal injury, hemorrhagic shock, or endotoxin challenge. Physical disruption of the mucosal barrier appears to be the key factor responsible for the promotion of bacterial translocation in all three of these nonlethal models. Since, in all three models, inhibition of inactivation of xanthine oxidase both reduces the extent of the mucosal injury and the incidence of bacterial translocation, we believe that xanthine oxidase-generated oxidants may play a major role in promoting bacterial translocation by disrupting mucosal integrity. Thus, the first two specific aims of this proposal will examine the hypothesis that bacterial translocation is due to ischemia/reperfusion-induced mucosal injury mediated by oxidants derived from either xanthine oxidase or activated neutrophils. Since luminal and/or translocating bacteria could potentiate the mucosal injury, the last specific aim will investigate whether or not the gut microflora influences the extent of mucosal injury in our three models of bacterial translocation. The investigations outlined in this proposal will help clarify the mechanisms that promote bacterial translocation from the gut. Also, we believe that a unique and important aspect of this proposal is that we are studying the biologic significance of the ischemia/reperfusion phenomenon in vivo. These basic studies are necessary to provide information for developing therapeutic strategies to prevent systemic infections by organisms colonizing the patient's gastrointestinal tract.